Our recent discovery of MTNR1B, encoding for the high-affinity melatonin receptor MT2, as a novel genetic risk variant for type 2 diabetes (T2D) and glycemic traits in genome wide association studies (GWAS) has sparked great interest in the role of melatonin in glycemic control. However, the exact mechanism is not yet understood. A major limitation in all previous GWAS is that the clinical assessment of T2D and of the glycemic traits are based on daytime assessments, when circulating concentrations of the ligand of the MT2 receptor, i.e., melatonin, are near-undetectable. The observed phenotypes of the MTNR1B risk variant may thus be the proverbial tip of the ice berg compared to its potential impact during the night when endogenous melatonin concentrations are approximately 20-fold higher or following exogenous melatonin administration. Indeed, while in GWAS we find the magnitude of effect of the MTNR1B risk variant on 2-h glucose concentrations following OGTT to be approximately 0.07 mmol/L, in our preliminary data, following exogenous melatonin administration in the morning elevating circulating levels to or beyond nighttime concentrations, this impact was approximately 15-fold larger (1.00 mmol/L). In this proposal, we overcome a number of limitations in prior work, and we aim to test the hypotheses that: (1) exogenous melatonin administration at a time that melatonin levels are normally low worsens glucose tolerance and insulin sensitivity; (2) this effect is stronger in the carriers of the common MTNR1B risk SNP compared to non-carriers; (3) the interaction of melatonin administration and genetic variance on glucose tolerance depends on time of day; (4) suppression of nighttime melatonin concentrations by light exposure during simulated night work improves glucose tolerance; and (5) this beneficial effect is stronger in the carriers of the common MTNR1B risk SNP compared to non-carriers. The hypotheses will be tested under highly controlled in-laboratory studies. To further investigate underlying mechanisms, we will perform parallel studies using ex vivo human pancreatic islets. This research will provide mechanistic insights into the effects of elevated melatonin concentrations concurrent with food intake as occurs in the 10% of the work force engaged in night shift work, in the millions of people who consume food after dinner when endogenous melatonin levels are elevated, and in people using exogenous melatonin against sleep disturbances, jet lag, and delayed sleep phase syndrome. In addition this research may help in the development of evidence-based countermeasures such as light exposure in the fight against T2D in shift workers and night eaters.